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Gestational Exposure to Chlordecone Promotes Transgenerational www.nature.com/scientificreports OPEN Gestational exposure to chlordecone promotes transgenerational changes in the Received: 16 January 2018 Accepted: 27 June 2018 murine reproductive system of Published: xx xx xxxx males Aurore Gely-Pernot1, Chunxiang Hao2, Louis Legof1, Luc Multigner1, Shereen Cynthia D’Cruz1, Christine Kervarrec1, Bernard Jégou1, Sergei Tevosian3 & Fatima Smagulova1 Environmental factors can afect epigenetic events during germline reprogramming and impose distinctive transgenerational consequences onto the ofspring. In this study, we examined the transgenerational efects of chlordecone (CD), an organochlorine insecticide with well-known estrogenic properties. We exposed pregnant mice to CD from embryonic day 6.5 to 15.5 and observed a reduction in spermatogonia (SG) numbers in F3, meiotic defects in spermatocytes and decrease in spermatozoa number in the frst and third generation of male progeny. The RNA qRT-PCR expression analysis in F1 and transcriptomics analysis in F3 males using the whole testes revealed changes in the expression of genes associated with chromosome segregation, cell division and DNA repair. The expression of the master regulator of pluripotency, Pou5f1, decreased in foetal and increased in adult F1, but not in F3 adult testes. Analysis of histone H3K4me3 distribution revealed widespread changes in its occupancy in the genome of F1 and F3 generations. We established that 7.1% of altered epigenetic marks were conserved between F1 and F3 generations. The overlapping changes common to F1 and F3 include genes implicated in cell adhesion and transcription factor activities functions. Diferential peaks observed in F1 males are signifcantly enriched in predicted ESR1 binding sites, some of which we confrmed to be functional. Our data demonstrate that CD-mediated impairment of reproductive functions could be transmitted to subsequent generations. During development, germ cells undergo comprehensive global somatic-to-germline reprogramming. Epigenetic modifcations, such as DNA methylation and histone modifcations are involved in this process. Te H3K4me3 and H3K27me3 histone marks are postulated to be key epigenetic modifcations that are located at the promoters of pluripotent genes in embryonic stem (ES) cells1. Despite their common occurrence in the regulatory regions, it was determined that the mere presence of H3K4me3 does not indicate or predict transcriptional activity1–3. Instead, it was hypothesized that enrichment for histone marks could serve to defne cell identity, with sub- sets of diferentially marked genes kept in a poised state in the germline during foetal development throughout post-meiotic stage4. In this case, H3K4me3 marks positioned at developmentally relevant genes are thought to be essential for germ cell identity, to defne the developmental window where transcription factors are recruited4. Importantly, while the bulk of histones are replaced by protamine in sperm, 1% in mice and up to 10% of histones in humans are retained in genomic DNA5. It is now widely accepted that remodelling of chromatin archi- tecture plays an important role in transgenerational inheritance (reviewed in6). Moreover, ectopic overexpression 1University Rennes, EHESP, Inserm, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000, Rennes, France. 2College of Pharmacy, Linyi University, 276000, Linyi, China. 3University of Florida, Department of Physiological Sciences Box 100144, 1333 Center Drive, 32610, Gainesville, FL, USA. Aurore Gely- Pernot, Chunxiang Hao and Louis Legof contributed equally to this work. Correspondence and requests for materials should be addressed to F.S. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:10274 | DOI:10.1038/s41598-018-28670-w 1 www.nature.com/scientificreports/ of the human histone lysine demethylase, KDM1a, during mouse spermatogenesis resulted in the transgenera- tional inheritance of abnormalities in the limbs, skeleton and skin development. Tis data supports the idea that histone methylation could be a mediator of transgenerational efects7. Te whole-genome datasets cataloguing human and bovine sperm nucleosome-retaining fractions provide evidence that genes encoding proteins with signal transduction and mitochondrial functions are enriched in the histone-containing parts of the genome8. Te enrichment of the same set of genes in both human and bovine genomes suggests a conserved mechanism for histone retention8. Subsequent work confrmed histone inheritance in sperm and is in agreement with the results of previous studies (e.g.9). Until recently, the ultimate fate of paternal histones in zygotes was unclear. Te ChIP STAR protocol, which allows the use of a very limited amount of nuclear material, was used to explore the fate and dynamics of paternal histones in early embryos9,10. Importantly, a low but detectable level of paternal H3K4me3 was present in early embryos, with histone peaks organized in large domains. It was postulated that these paternal H3K4me3 histones existed during a poised state and that the genes corresponding to these marks were wait- ing to be activated10. In line with this prediction, during the early embryonic stage, bivalently marked histones are absent at the regulatory regions governing developmental genes and subsequently become re-established in post-implantation embryos9. Skinner and colleagues demonstrated that several toxic compounds could promote epigenetic changes that are detected in subsequent generations11–13. In our recent study, we showed that embryonic exposure to the herbicide atrazine (ATZ) causes global changes in gene expression in several tissues in the third (F3) generation, with the testis harbouring the largest number of diferentially expressed transcripts14. We also found that altered RNA expression in the testes is associated with global changes in histone H3K4me3 localization, providing further support for the idea that transgenerational efects can be mediated by the retention of histones in a small fraction of the genome14. Diferential epigenetic marks were found at the Pou5f1, Phf2, Ezh2 and Zhx2 genes, which are essential for establishing the pluripotent state of germ cells14. Tese data suggest a possible role for epigenetic modifcations in the transmission of ATZ efects to subsequent generations. Epigenetic mechanisms are presumed to include other heritable alterations including noncoding RNA and DNA methylation15. Tere is evidence that all of these mechanisms can be used to transmit environmentally-induced modifcations across several genera- tions via gamete inheritance (reviewed in16). In this study, we examined whether the transgenerational efects could be promoted by the insecticide CD, also known as Kepone. CD was extensively used in the USA, Latin America, Africa and Eastern Europe until 1975, and, until 1993, in the French West Indies. Because CD does not undergo biotic or abiotic degradation in the environment, permanently polluted soil and waters are the primary source of food contamination, and humans remain exposed to this chemical in the French West Indies. CD causes hepatic tumours in laboratory rats and mice17–19 and has neurotoxic efects in rats20. Furthermore, CD is capable of binding with oestrogen receptors ESR1 and ESR2, eliciting agonistic and antagonistic efects respectively21,22. Activation of ESR1 mediates adverse efects of oestrogen, such as aberrant proliferation, infammation, and malignancy; whereas ESR2 is thought to exert the opposite efects, such as anti-proliferative, anti-infammatory, and potentially anti-carcinogenic activi- ties23. Hence, CD’s engagement of ESRs can trigger aberrant responses by engaging oestrogen signalling cascades. In humans, occupational exposure to CD at high doses causes neurological problems and decreases sperm cell production and motility24,25. Epidemiological studies have suggested that continuous exposure to CD at environ- mental levels in adults could also increase the risk of prostate cancer26. Of particular concern is the ability of CD to cross the placenta and afect the embryo, as many developmental processes are vulnerable to its efects. Gestational exposure to CD afects prenatal and postnatal development in rats and mice (reviewed in27). Recent data from the TIMOUN Mother-Child Cohort Study conducted in French West Indies show that prenatal exposure to CD at environmental levels is associated with a decreased length of gestation28 and may afect foetal and infant growth29 as well as neurodevelopment during infancy30,31. Because CD is persistent in nature, and human populations are still exposed to the compound, it is important to evaluate its ability to afect transgenerational inheritance. We hypothesized that developmental exposure to a low dose of CD could afect germ cells during the reprogramming window and that these changes could be transmitted to subsequent generations. During reprograming window germ cells are known to undergo exten- sive epigenetic modifcation of their genome and chromatin and to acquire the pluripotent state. In mice, this process occurs between embryonic days (E) E5.5 and E15, and is initiated by the expression of transcription factor BLIMP1/PRDM1 (for review, see32. PRDM1 represses the somatic program and promotes the progression towards germ cell diferentiation33. Here, we show that gestational exposure to CD decreases SG cell numbers, afects meiosis, leads to changes in RNA expression and alters H3K4me3 occupancy at many genes in the frst and third generation
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